Intricate mechanisms regulate mRNA synthesis by control of initiation or elongation of transcription. An understanding of these mechanisms and the factors controlling these mechanisms would be important in designing therapeutic modalities for treating a variety of important medical conditions, including cancer and infection. For example, HIV-1 transcriptional elongation by Tat is essential for viral replication. Interruption of transcriptional elongation by Tat, therefore, would be highly desirable as a means for treating HIV-infected individuals.
Tat activation of HIV-1 transcription is mechanistically different from conventional activation of transcription by DNA sequence-specific transcription factors. First, most conventional activators affect transcription primarily through increasing the rate of initiation, although recent studies indicate that some prototype DNA sequence-specific transcription factors such as GAL4-VP16 can stimulate both initiation and elongation. In contrast, Tat predominantly stimulates the efficiency of elongation. Secondly, while most conventional activators interact with promoter or enhancer DNA, Tat interacts with the trans-acting responsive (TAR) RNA element. TAR is located at the 5' end of the nascent viral transcript and forms a stem-loop structure. The specific binding of Tat to TAR depends primarily upon the integrity of the bulge loop and immediately flanking sequences in the double-stranded RNA. Sequences in the apical loop of TAR are also important for Tat activation of transcription in vivo.
Control of transcriptional elongation thus has been recognized as an important step in gene regulation, but mechanisms regulating the efficiency of elongation, mediated by RNA polymerase II, have not been extensively studied. The necessity for strict control of elongation for proper gene regulation is further highlighted by the recent finding that an elongation factor, Elongin, is probably the functional target of the von Hippel-Lindau tumor suppressor protein.